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Adipose-derived Stem cell/FGF19-loaded microfluidic hydrogel microspheres for synergistic restoration of critical ischemic limb

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Bioactive Materials 2023年第9期27卷 394-408页

作者： Ruihan Wang Fangqian Wang Shan Lu Bin Gao Yuanqing Kan Tong Yuan Yisheng Xu Chen Yuan Daqiao Guo Weiguo Fu Xiaohua Yu Yi Si Department of Vascular Surgery Zhongshan Hospital Fudan UniversityShanghai200032PR China Institute of Vascular Surgery Fudan UniversityShanghai200032PR China National Clinical Research Center for Interventional Medicine Shanghai200032PR China Department of Orthopedics The Second Affiliated Hospital of Zhejiang University School of MedicineHangzhou310009ZhejiangPR China Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province Hangzhou310000ZhejiangPR China State Key Laboratory of Chemical Engineering East China University of Science and TechnologyShanghai200237China

The efficacy of Stem cell therapy is substantially compromised due to low cell survival rate and poor local retention post-delivery. These issues drastically limit the application of Stem cells for ischemic limb therapy, which requires effective blood perfusion and skeletal muscle regeneration. Herein, based on microfluidic technology, an integrated Stem cell and cytokine co-delivery system designed for functional ischemic limb salvage was constructed by first incorporating the myogenic cytokine, fibroblast growth factor 19 (FGF19), into microspheres composed of methacrylate gelatin (GelMA). Then adipose-derived Stem cells (ADSCs) were highly absorbed into the porous structure of the microspheres, overcoming the insufficient loading efficiency and activities by conventional encapsulation strategy. The fabricated ADSCs/FGF19@μsphere system demonstrated a uniform size of about 180 μm and a highly porous structure with pore sizes between 20 and 40 μm. The resultant system allowed high doses of ADSCs to be precisely engrafted in the lesion and to survive, and achieved sustained FGF19 release in the ischemic region to facilitate myoblast recruitment and differentiation and myofibrils growth. Furthermore, the combination of ADSCs and FGF19 exhibited a positive synergistic effect which substantially improved the therapeutic benefit of angiogenesis and myogenesis, both in vitro and in vivo. In summary, a Stem cell and cytokine co-delivery system with the properties of easy preparation and minimal invasiveness was designed to ensure highly efficient cell delivery, sustained cytokine release, and ultimately realizes effective treatment of ischemic limb regeneration.

关键词： Microfluidic technology Stem cell Cytokine Porous microspheres Ischemic limb salvage

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Stem cell niche-inspired microcarriers with ADSCs encapsulation for diabetic wound treatment

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Bioactive Materials 2023年第8期26卷 159-168页

作者： Xiangyi Wu Haofang Zhu Junyi Che Ye Xu Qian Tan Yuanjin Zhao Department of Burns and Plastic Surgery Institute of Translational MedicineThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing210002China Oujiang Laboratory(Zhejiang Lab for Regenerative Medicine Vision and Brain Health)Wenzhou InstituteUniversity of Chinese Academy of SciencesWenzhouZhejiang325000China

Stem cell therapies have made great progress in the treatment of diabetic wounds during recent decades,while their short in vivo residence,alloimmune reactions,undesired behaviors,and dramatic losses of cell functions still hinder the translation of them into clinic.Here,inspired by the natural components of Stem cell niches,we presented novel microfluidic hydrogel microcarriers with extracellular matrix(ECM)-like composition and adipose-derived Stem cells(ADSCs)encapsulation for diabetic wound healing.As the hydrogel was synthesized by conjugating hyaluronic acid methacryloyl(HAMA)onto the Fibronectin(FN)molecule chain(FN-HAMA),the laden ADSCs in the microcarriers showed improved bioactivities and pro-regenerative capabilities.Based on these features,we have demonstrated that these ADSCs microcarriers exhibited significant promotion of neovascularization,follicular rejuvenation,and collagen deposition in a mouse diabetic wound model.These results indicated that the Stem cell niche-inspired FN-HAMA microcarriers with ADSCs encapsulation have great clinical potential for diabetic wound treatment.

关键词： Stem cell Bio-inspired Microfluidics Microcarrier Wound healing Hydrogel

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Intranasal administration of Stem cell-derived exosomes for central nervous system diseases

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Neural Regeneration Research 2024年第6期19卷 1249-1255页

作者： Shuho Gotoh Masahito Kawabori Miki Fujimura Department of Neurosurgery Hokkaido University Graduate School of Medicine

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from Stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including antiapoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over Stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of Stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosomebased treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

关键词： central nervous system disease exosome extracellular vesicle intranasal administration Stem cell

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Stem cell therapy in retinal diseases

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Neural Regeneration Research 2023年第7期18卷 1478-1485页

作者： Audrey Voisin Amaury Pénaguin Afsaneh Gaillard Nicolas Leveziel Laboratoire de Neurosciences Expérimentales et Cliniques Universitéde PoitiersINSERM 1084PoitiersFrance Department of Ophthalmology CHU PoitiersPoitiersFrance Laboratoires Thea Clermont-FerrandFrance

Alteration of the outer retina leads to various diseases such as age-related macular degeneration or retinitis pigmentosa characterized by decreased visual acuity and ultimately blindness.Despite intensive research in the field of retinal disorders,there is currently no curative treatment.Several therapeutic approaches such as cell-based replacement and gene therapies are currently in development.In the context of cell-based therapies,different cell sources such as embryonic Stem cells,induced pluripotent Stem cells,or multipotent Stem cells can be used for transplantation.In the vast majority of human clinical trials,retinal pigment epithelial cells and photoreceptors are the cell types considered for replacement cell therapies.In this review,we summarize the progress made in Stem cell therapies ranging from the pre-clinical studies to clinical trials for retinal disease.

关键词： age-related macular degeneration cell transplantation clinical trial retinal disease retinal dystrophy Stem cell

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Techniques for increasing the yield of Stem cell-derived exosomes:what factors may be involved?

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Science China(Life Sciences) 2022年第7期65卷 1325-1341页

作者： Zi-Yuan Feng Qing-Yi Zhang Jie Tan Hui-Qi Xie Laboratory of Stem cell and Tissue Engineering Orthopedic Research InstituteMed-X Center for MaterialsState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengdu 610041China

Exosomes are nano-scale extracellular vesicles secreted by cells and constitute an important part in the cell-cell communication.The main contents of the exosomes include proteins,micro RNAs,and lipids.The mechanism and safety of Stem cell-derived exosomes have rendered them a promising therapeutic strategy for regenerative medicine.Nevertheless,limited yield has restrained full explication of their functions and clinical applications.To address this,various attempts have been made to explore the up-and down-stream manipulations in a bid to increase the production of exosomes.This review has recapitulated factors which may influence the yield of Stem cell-derived exosomes,including selection and culture of Stem cells,isolation and preservation of the exosomes,and development of artificial exosomes.

关键词： exosome Stem cell yield therapy

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Pulmonary endogenous progenitor Stem cell subpopulation:Physiology,pathogenesis,and progress

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Journal of Intensive Medicine 2023年第1期3卷 38-51页

作者： Di Liu Chufan Xu Lai Jiang Xiaoyan Zhu Department of Anesthesiology and Surgical Intensive Care Unit Xinhua HospitalShanghai Jiaotong University School of MedicineShanghai 200092China Department of Physiology Navy Medical University800 Xiangyin RoadShanghai 200433China

Lungs are structurally and functionally complex organs consisting of diverse cell types from the proximal to distal axis.They have direct contact with the external environment and are constantly at risk of various injuries.Capable to proliferate and differentiate,pulmonary endogenous progenitor Stem cells contribute to the maintenance of lung structure and function both under homeostasis and following injuries.Discovering candidate pulmonary endogenous progenitor Stem cell types and underlying regenerative mechanisms provide insights into therapeutic strategy development for lung diseases.In this review,we reveal their compositions,roles in lung disease pathogenesis and injury repair,and the underlying mechanisms.We further underline the advanced progress in research approach and potential therapy for lung regeneration.We also demonstrate the feasibility and prospects of pulmonary endogenous Stem cell transplantation for lung disease treatment.

关键词： Stem cell Lung diseases Lung injury Regeneration Repair

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CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts human mesenchymal Stem cell senescence

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Science China(Life Sciences) 2024年第3期67卷 460-474页

作者： Daoyuan Huang Qian Zhao Kuan Yang Jinghui Lei Ying Jing Hongyu Li Chen Zhang Shuai Ma Shuhui Sun Yusheng Cai Guibin Wang Jing Qu Weiqi Zhang Si Wang Guang-Hui Liu Advanced Innovation Centerfor Human Brain Protection National Clinical Research Centerfor Geriatric DisordersXuanwu Hospital Capital Medical UniversityBeijing 100053China State Key Laboratory of Stem cell and Reproductive Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China Aging Translational MedicineCenter International Centerfor Aging and CancerBejing Municipal GeriatricMedical Research CenterXuanwu HospitalCapital Medical UniversityBeijing 100053China State Key Laboratory of Membrane Biology Institute of ZoologyChinese Academy of SciencesBeijing 100101China University of Chinese Academy of Sciences Beijing 100049China Beijing Institute for Stem cell and Regenerative Medicine Beijing100101China CAS Key Laboratory of Genomic and Precision Medicine Bejing Institute of Genomics and China National Center for BioinformationChinese Academy of SciencesBeijing 100101China Institute for Stem cell and Regeneration CASBeijing 100101China The Fifth People's Hospital of Chongqing Chongqing 400062China Sino-Danish Cllege University of Chinese Academy of SciencesBeijing101408China National Laboratory of Biomacromolecules CAS Center for Excelence in BiomacromoleculesInstitute of BiophysicsChinese Academy of SciencesBeijing100101China State Key Laboratory of Proteomics Beijing Proteome Research CenterNational Center for Protein Sciences(Beijing)Beijing Institute of LifeomicsBeijing 102206China

Cullin-RING E3 ubiquitin ligases(CRLs),the largest family of multi-subunit E3 ubiquitin ligases in eukaryotic cells,represent core cellular machinery for executing protein degradation and maintaining proteostasis.Here,we asked what roles Cullin proteins play in human mesenchymal Stem cell(hMSC)homeostasis and senescence.To this end,we conducted a comparative aging phenotype analysis by individually knocking down Cullin members in three senescence models:replicative senescent hMSCs,Hutchinson-Gilford Progeria Syndrome hMSCs,and Werner syndrome hMSCs.Among all family members,we found that CUL2 deficiency rendered hMSCs the most susceptible to senescence.To investigate CUL2-specific underlying mechanisms,we then applied CRISPR/Cas9-mediated gene editing technology to generate CUL2-deficient human embryonic Stem cells(hESCs).When we differentiated these into h MSCs,we found that CUL2 deletion markedly accelerates hMSC senescence.Importantly,we identified that CUL2 targets and promotes ubiquitin proteasome-mediated degradation of TSPYL2(a known negative regulator of proliferation)through the substrate receptor protein APPBP2,which in turn downregulates one of the canonical aging marker-P21^(waf1/cip1),and thereby delays senescence.Our work provides important insights into how CRL2^(APPBP2)-mediated TSPYL2 degradation counteracts hMSC senescence,providing a molecular basis for directing intervention strategies against aging and aging-related diseases.

关键词： Cullins Stem cell senescence aging proteostasis ubiquitination APPBP2 TSPYL2

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Chronic wounds:pathological characteristics and their Stem cell-based therapies

再生工程(英文)

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再生工程(英文) 2023年第1期4卷 81-94页

作者： Xiangyi Wu Haofang Zhu Ye Xu Bin Kong Qian Tan Department of Burns and Plastic Surgery Institute of Translational MedicineThe Affiliated Drum Tower Hospital of Nanjing University Medical SchoolNanjing 210002China Guangdong Key Laboratory for Biomedical Measurements and Ultrasound Imaging Department of Biomedical Engineering School of MedicineShenzhen UniversityShenzhen 518060China

Chronic wounds are characterized by prolonged healing processes and poor prognoses,which have substantially impacted human health and daily life.Traditional treatment strategies have various limitations and drawbacks.Therefore,fully effective therapeutic approaches remain urgently needed.Stem cell(SC)-based therapies have drawn significant attention for their abilities of immunomodulation and pro-regeneration.It has been demon-strated that Stem cells(SCs)can improve angiogenesis,collagen deposition,and hair rejuvenation,thus facilitating wound healing.In addition,attempts were performed to facilitate the cell survival,function,retention,and en-graftment of the delivered SCs.In this review,we first introduce the pathological process involved in chronic wound healing.Following that,the mechanism of SCs in promoting chronic wound repair is discussed in detail.Then,we highlight recent SC-based therapies for chronic wound repair developments.Finally,we present our views on the remaining challenges and future trends of SC-based therapies for chronic wound treatment.

关键词： Chronic wounds Stem cell cell scaffold cell-free therapy Gene modification

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The pre-mRNA splicing factor RDM16 regulates root Stem cell maintenance in Arabidopsis

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Journal of Integrative Plant Biology 2021年第4期63卷 662-675页

作者： Bingsheng Lv Kongqin Hu Te Tian Kaijing Wei Feng Zhang Yuebin Jia Huiyu Tian Zhaojun Ding The Key Laboratory of Plant Development and Environmental Adaptation Biology Ministry of EducationSchool of Life SciencesShandong UniversityQingdao 266237China Shandong Provincial Key Laboratory of Plant Stress College of Life SciencesShandong Normal UniversityJinan 250014China

Pre-mRNA(messenger RNA)splicing participates in the regulation of numerous biological processes in plants.For example,alternative splicing shapes transcriptomic responses to abiotic and biotic stress,and controls developmental programs.However,no study has revealed a role for splicing in maintaining the root Stem cell niche.Here,a screen for defects in root growth in Arabidopsis thaliana identified an ethyl methane sulfonate mutant defective in pre-m RNA splicing(rdm16-4).The rdm16-4 mutant displays a short-root phenotype resulting from fewer cells in the root apical meristem.The PLETHORA1(PLT1)and PLT2 transcription factor genes are important for root development and were alternatively spliced in rdm16-4 mutants,resulting in a disordered root Stem cell niche and retarded root growth.The root cap of rdm16-4 contained reduced levels of cytokinins,which promote differentiation in the developing root.This reduction was associated with the alternative splicing of genes encoding cytokinin signaling factors,such as ARABIDOPSIS HISTIDINE PHOSPHOTRANSFER PROTEIN5 and ARABIDOPSIS RESPONSE REGULATORS(ARR1,ARR2,and ARR11).Furthermore,expression of the full-length coding sequence of ARR1 or exogenous cytokinin application partially rescued the short-root phenotype of rdm16-4.This reveals that the RDM16-mediated alternative splicing of cytokinin signaling components contributes to root growth.

关键词： cytokinin Pre-mRNA splicing PLETHORA RDM16 root growth Stem cell

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Secretome-microRNA and anti-proliferative APRO family proteins as cancer prevention and Stem cell research strategies

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BIOcell 2022年第5期46卷 1163-1167页

作者： YUKA IKEDA NOZOMI NAGASE AI TSUJI KURUMI TANIGUCHI YASUKO KITAGISHI SATORU MATSUDA Department of Food Science and Nutrition Nara Women’s UniversityNara630-8506Japan

stemness of cancer cells contains limitless self-renewal proliferation.For the purpose of proliferation,secretome might exert its effects via the paracrine signaling.Specific microRNAs enclosed in the secretome of cancer Stem cells could regulate the expression of anti-proliferative APRO family proteins.The biological functions of APRO family proteins seems to be quite intricate,however,which might be a key modulator of microRNAs,then could regulate the proliferation of cancer cells.In addition to affecting proliferation/differentiation during cellular development,APRO family proteins might also play an imperious role on keeping homeostasis in healthy Stem cells under a physiological condition.Therefore,relationship between the microRNAs and the APRO family proteins has attracted much attention in the field of cancer research and regenerative medicine.Here,we have described the molecular mechanism behind this interplay that have a potential role in the future promising tools with targeting APRO family proteins for the medical applications.

关键词： Cancer Stem cell Secretome Proliferation APRO family microRNA

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